Search Results (332)

Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration. Full article

Parkinson’s disease (PD) is recognized as one of the most common neurodegenerative disorders globally. The primary factor contributing to this condition is the loss of dopaminergic neurons, which results in both motor and nonmotor symptoms. The etiology of neurodegeneration remains unclear. However, it is characterized by the elevated production of reactive oxygen species, which subsequently leads to oxidative stress, lipid peroxidation, mitochondrial dysfunction, and inflammation. The investigation of the applicability of natural compounds and their derivatives to various diseases is becoming increasingly important. The possible role of curcumin from Curcuma longa L. and its derivatives in the treatment of PD has been partially investigated, but there are no data on the action of synthetic cyclic C₅-curcuminoids and chalcones tested in a Parkinson’s model. Two chalcones and five synthetic cyclic C₅-curcuminoids with potential antioxidant properties were investigated in an in vitro model of 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in differentiated SH-SY5Y cells. Reactive oxygen species (ROS) production, total antioxidant capacity, antioxidant enzyme activity, thiol and ATP levels, caspase-3 activity, and cytokine release were examined after treatment with the test compounds. Based on these results, one cyclic chalcone (compound 5) and three synthetic cyclic C₅-curcuminoids (compounds 9, 12, and 13) decreased oxidative stress and apoptosis in our in vitro model of neurodegeneration. Compounds 5 and 9 were also successful in decreasing the production of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while promoting the release of anti-inflammatory cytokines (IL-4 and IL-10). These findings indicate that these two compounds exhibit potential antioxidant, anti-apoptotic, and anti-inflammatory properties, rendering them promising candidates for drug development. Full article

Glaucoma is traditionally classified as an ocular disease characterized by progressive retinal ganglion cell (RGC) loss and optic nerve damage. However, emerging evidence suggests that its pathophysiology may extend beyond the eye, involving trans-synaptic neurodegeneration along the visual pathway and structural changes within central brain regions, including the lateral geniculate nucleus and visual cortex. In this narrative review, we have used the phrase ‘brain involvement’ to underscore central changes that accompany or follow retinal ganglion cell loss; we have not intended to redefine glaucoma as a primary cerebral disorder. Neuroimaging studies and neurocognitive assessments in adult glaucoma patients, primarily older individuals with primary open-angle glaucoma reveal that glaucoma patients may exhibit alterations in brain connectivity and cortical thinning, aligning it more closely with neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. This evolving neurocentric perspective raises important questions regarding shared mechanisms—such as mitochondrial dysfunction, chronic inflammation, and impaired axonal transport—that may link glaucomatous optic neuropathy to central nervous system (CNS) pathology. These insights open promising therapeutic avenues, including the repurposing of neuroprotective and neuroregenerative agents, targeting not only intraocular pressure (IOP) but also broader CNS pathways. Furthermore, neuroimaging biomarkers and brain-targeted interventions may play a future role in diagnosis, prognosis, and individualized treatment. This review synthesizes current evidence supporting glaucoma as a CNS disease, explores the mechanistic overlap with neurodegeneration, and discusses the potential clinical implications of glaucoma within a neuro-ophthalmologic paradigm. Full article

Catalase, a pivotal antioxidant enzyme, plays a central role in converting hydrogen peroxide (H₂O₂) into oxygen and water, thereby safeguarding cells from oxidative damage. In patients with diabetes, obesity, Alzheimer’s disease (AD), and Parkinson’s disease (PD), catalase becomes increasingly susceptible to non-enzymatic glycation, resulting in enzyme inactivation, oxidative stress, and defective mitochondrial function. This review uniquely emphasizes catalase glycation as a converging pathological mechanism that bridges metabolic and neurodegenerative disorders, underscoring its translational significance beyond prior general reviews on catalase function. In patients with metabolic diseases, glycation impairs β-cell function and insulin signaling, while in patients with neurodegeneration, it accelerates protein aggregation, mitochondrial dysfunction, and neuroinflammation. Notably, the colocalization of glycated catalase with amyloid-β and α-synuclein highlights its potential role in protein aggregation and neuronal toxicity, a mechanism not previously addressed. Therapeutically, targeting catalase glycation opens up new avenues for intervention. Natural and synthetic agents can be used to protect catalase activity by modulating glyoxalase activity, heme integrity, or carbonyl stress. Vitamins C and E, along with agents like sulforaphane and resveratrol, exert protection through complementary mechanisms, beyond ROS scavenging. Moreover, novel strategies, including Nrf2 activation and receptor for advanced glycation end products (RAGE) inhibition, are showing promise in restoring catalase activity and halting disease progression. By focusing on glycation-specific mechanisms and proposing targeted therapeutic approaches, this review positions catalase glycation as a novel and clinically relevant molecular target in patients with chronic diseases and a viable candidate for translational research aimed at improving clinical outcomes. Full article

In recent times, neurodegenerative diseases have become a global health concern, particularly among the elderly. This may be attributed to the increased risk of neuronal death due to age. Moreover, the underlying mechanisms of neurodegeneration are largely driven by age-related processes that include oxidative stress, mitochondrial dysfunction, and inflammation. Despite extensive research efforts, however, neurodegenerative disorders still remain incurable as current therapeutic strategies provide limited efficacy as well as severe side effects. For these reasons, dietary phytochemicals are being considered as preventive strategies because they have potential neuroprotective functions against age-related neurodegeneration. This review summarizes the mechanisms underlying age-related neurodegeneration and highlights the current challenges in their treatment and management. It also discusses the potential of dietary phytochemicals as complementary interventions, focusing on their neuroprotective functions and mechanisms of action. Finally, challenges surrounding the use of dietary phytochemical interventions in controlling age-related neurodegenerative disorders are addressed and solutions to these challenges based on available research are discussed. Full article

Hypoxic stress is increasingly recognized as a convergent pathological factor in various age-related neurodegenerative diseases (NDDs), encompassing both acute events such as stroke and traumatic brain injury (TBI), and chronic disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). Recent studies have revealed that hemoglobin (Hb), beyond its classical oxygen-transport function, exhibits unexpected expression and functional relevance within the central nervous system. Notably, both cerebral and circulating Hb appear to be dysregulated under hypoxic and aging conditions, potentially influencing disease onset and progression of these diseases. However, Hb’s impact on neurodegeneration appears to be context-dependent: in acute NDDs, it may exert neuroprotective effects by stabilizing mitochondrial and iron homeostasis, whereas in chronic NDDs, aberrant Hb accumulation may contribute to toxic protein aggregation and neuronal dysfunction. This review provides an integrative overview of the emerging roles of Hb in hypoxia-related NDDs, highlighting both shared and distinct mechanisms across acute and chronic conditions. We further discuss potential therapeutic implications of targeting Hb-related pathways in NDDs and identify key gaps for future investigation. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD) are closely linked to oxidative stress and advanced glycation end products (AGEs), two interrelated processes that exacerbate neuronal damage through mitochondrial dysfunction, protein aggregation, and chronic inflammation. This narrative review explores the metabolic interplay between reactive oxygen species (ROS) and AGEs, with a focus on the AGE-RAGE (receptor for advanced glycation end products) signaling axis as a driver of neurodegeneration. Evidence from preclinical and clinical studies highlights their combined role in disease progression and underscores potential therapeutic targets. Strategies including mitochondria-targeted antioxidants, AGE inhibitors, RAGE antagonists, and metabolic interventions are discussed, along with future directions for biomarker development and personalized treatments. This review integrates current molecular insights into a unified metabolic–inflammatory model of AD, highlighting translational therapeutic opportunities. Full article

Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization—spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways—including PI3K–AKT–mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades—undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome–lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3–CR3 axis), and excitatory–inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network “meaning-making”—a collapse of coordinated signal interpretation, triage prioritization, and adaptive response—the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning—a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration. Full article

Aging, a state of progressive decline in physiological function, is an important risk factor for chronic diseases, ranging from cancer and musculoskeletal frailty to cardiovascular and neurodegenerative diseases. Understanding its cellular basis is critical for developing interventions to extend human health span. This review highlights the crucial role of in vitro models, discussing foundational discoveries like the Hayflick limit and the senescence-associated secretory phenotype (SASP), the utility of immortalized cell lines, and transformative human induced pluripotent stem cells (iPSCs) for aging and disease modeling and rejuvenation studies. We also examine methods to induce senescence and discuss the distinction between chronological time and biological clock, with examples of applying cells from progeroid syndromes and mitochondrial diseases to recapitulate some signaling mechanisms in aging. Although no in vitro model can perfectly recapitulate organismal aging, well-chosen models are invaluable for addressing specific mechanistic questions. We focus on experimental strategies to manipulate cellular aging: from “steering” cells toward resilience to “reversing” age-related phenotypes via senolytics, partial epigenetic reprogramming, and targeted modulation of proteostasis and mitochondrial health. This review ultimately underscores the value of in vitro systems for discovery and therapeutic testing while acknowledging the challenge of translating insights from cell studies into effective, organism-wide strategies to promote healthy aging. Full article

Periodontitis, a chronic inflammatory disease affecting the supporting tissues of the teeth, has been linked to the onset of neurological diseases, including Alzheimer’s disease (AD). A primary mechanism connecting these two issues is oxidative stress caused by an imbalance between antioxidant defenses and reactive oxygen species (ROS) synthesis. This review compiles results from both animal and human studies that explore how oxidative stress resulting from periodontitis leads to neuroinflammation, mitochondrial dysfunction, and cognitive decline in AD. Studies in animals indicate that periodontal infections worsen brain oxidative damage, as evidenced by elevated lipid peroxidation markers, such as malondialdehyde (MDA), and indicators of oxidative DNA damage, including 8-hydroxy-2′-deoxyguanosine (8-OHdG). Additionally, significant reductions in crucial antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase, along with neuroinflammation and cognitive deficits, are observed in mouse models of induced periodontitis. Supporting evidence from human studies reveals lower total antioxidant capacity (TAC) in individuals with both Alzheimer’s disease (AD) and periodontitis, as well as increased systemic oxidative stress markers, such as advanced oxidation protein products (AOPRs). These findings suggest a mechanistic relationship through oxidative stress pathways between periodontal inflammation and neurodegeneration. Given the extensive impact of periodontitis, enhancing periodontal health could be a viable strategy to reduce oxidative damage and lower the risk of cognitive decline. Further research is needed to clarify causality and to investigate antioxidant treatments aimed at preventing or slowing the progression of AD in patients with periodontal disease. Full article

Traumatic Brain Injury (TBI) is a major global health concern and a leading cause of death and disability, especially in young adults. It triggers complex secondary injury cascades, e.g., calcium dysregulation, mitochondrial dysfunction and protease activation, that extend well beyond the initial mechanical insult to drive ongoing neurodegeneration. The calcium-dependent protease calpain has emerged as a central mediator of TBI cellular pathology. Calpain cleaves a broad range of cytoskeletal and regulatory proteins across neuronal compartments, disrupting axonal integrity, synaptic function and calcium homeostasis. Despite decades of research, calpain remains an elusive therapeutic target. In this review, we examine the spatial and temporal patterns of calpain activation in the traumatically injured brain, categorize key calpain substrates by structure and location, and assess their mechanistic roles in TBI pathology. We also review recent advances in next-generation calpain-2 selective inhibitors with enhanced specificity and preclinical efficacy and discuss the emerging use of calpain-cleaved protein fragments such as SBDP145 and SNTF as candidate biomarkers for TBI diagnosis and progression. Drawing on molecular, preclinical, and clinical data, we argue that calpain warrants renewed attention as both a therapeutic target and mechanistic biomarker in TBI. It may be time for Cinderella to leave the basement. Full article

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, psychiatric disturbances, and cognitive decline. The pathophysiology of HD centers on a polyglutamine expansion in the huntingtin protein, which triggers widespread transcriptional dysregulation, impaired proteostasis, mitochondrial dysfunction, and excitotoxic neuronal loss—most prominently within the striatum and cortex. Despite decades of research, disease-modifying therapies remain elusive. This review synthesizes how the emerging integration of translational bioinformatics, spotlighting artificial intelligence-driven transcriptomic analyses, has identified transcriptional signatures correlating with disease progression and therapeutic response. These integrative approaches hold promise for accelerating the bench-to-bedside translation of HD therapeutics, positioning AI-powered discovery as a frontier for overcoming the complexity of neurodegeneration. Full article

Background: The mitochondrial integrated stress response (ISR) represents a fundamental cellular adaptation mechanism with dual protective and pathological roles. We critically analyzed current literature on ISR mechanisms, focusing on recent paradigm shifts including the 2020 discovery of the OMA1-DELE1-HRI axis, emerging controversies over context-dependent activation patterns, and the January 2025 clinical trial failures that have reshaped the therapeutic landscape. Methods: We reviewed recent literature (2020–2025) examining ISR mechanisms, clinical trials, and therapeutic developments through comprehensive database searches. Results: The field has evolved from simple linear pathway models to recognition of complex, context-dependent networks. Recent findings reveal that ISR activation mechanisms vary dramatically based on cellular metabolic state, with distinct pathways operating in proliferating versus differentiated cells. The “dark microglia” phenotype in neurodegeneration and DR5-mediated apoptotic switches exemplify pathological ISR manifestations, while adaptive responses include metabolic reprogramming and quality control enhancement. Conclusions: The 2025 failures of DNL343 and ABBV-CLS-7262 in ALS trials underscore the need for precision medicine approaches that account for context-dependent ISR functions, temporal dynamics, and disease-specific mechanisms. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and a major global health challenge, characterized by progressive cognitive decline and neurodegeneration. Despite decades of research, there is currently no cure, and available treatments provide only limited symptomatic relief without halting disease progression. In this context, natural compounds with multi-targeted biological activities are being explored as potential complementary therapeutic strategies. Honey, a complex natural substance rich in bioactive phytochemicals, has emerged as a promising candidate due to its antioxidant, anti-inflammatory, anti-apoptotic, and enzyme-inhibitory properties. This review summarizes the molecular mechanisms underlying the neuroprotective effects of honey in the context of AD, with a particular focus on its ability to modulate oxidative stress, mitochondrial dysfunction, inflammation, apoptosis, β-amyloid accumulation, tau hyperphosphorylation, and neurotransmission-related enzymes. Notably, the botanical origin of honey significantly influences its composition and biological activity, as evidenced by studies on avocado, manuka, acacia, kelulut, chestnut, coffee, or tualang honeys. While preclinical findings are encouraging, especially in vitro and in invertebrate and rodent models, clinical validation is still lacking. Therefore, further research, including well-designed in vivo and human studies, is needed to clarify the therapeutic relevance of honey in AD. Overall, honey may represent a promising natural adjunct in the prevention or management of AD, but current evidence remains preliminary. Full article

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article